Editing Nicotine (section)

==Chemistry==
{{NFPA 704|Health=4|Flammability=1|Reactivity=0|caption=The fire diamond hazard sign for nicotine<ref>{{cite web|url=http://www.nmsu.edu/safety/programs/chem_safety/NFPA-ratingJ-R.htm|title=NFPA Hazard Rating Information for Common Chemicals |access-date=15 March 2015|archive-url=https://web.archive.org/web/20150217040510/http://www.nmsu.edu/safety/programs/chem_safety/NFPA-ratingJ-R.htm|archive-date=17 February 2015}}</ref>}}

Nicotine is a [[hygroscopy|hygroscopic]], colorless<ref name=":4" /> to yellow-brown, oily liquid, that is readily soluble in alcohol, ether or light petroleum. It is [[miscible]] with [[water (molecule)|water]] in its neutral amine [[base (chemistry)|base]] form between 60&nbsp;°C and 210&nbsp;°C. It is a dibasic [[nitrogenous base]], having K<sub>b1</sub>=1×10<sup>−6</sup>, K<sub>b2</sub>=1×10<sup>−11</sup>.<ref name="metcalf"/> It readily forms ammonium [[salt (chemistry)|salts]] with [[acid]]s that are usually solid and water-soluble. Its [[flash point]] is 95&nbsp;°C and its auto-ignition temperature is 244&nbsp;°C.<ref name=SLMSDS>{{cite web | url = http://www.sciencelab.com/msds.php?msdsId=9926222 | title =  L-Nicotine Material Safety Data Sheet | work = Sciencelab.com, Inc. }}</ref> Nicotine is readily volatile ([[vapor pressure]] 5.5 Pa at 25&nbsp;°C)<ref name="metcalf"/> On exposure to ultraviolet light or various oxidizing agents, nicotine is converted to nicotine oxide, [[nicotinic acid]] (niacin, a B3 vitamer), and [[methylamine]].<ref name="library.sciencemadness.org"/>

Nicotine is [[Chirality (chemistry)|chiral]] and hence [[optically active]], having two [[enantiomer]]ic forms. The naturally occurring form of nicotine is [[levorotatory]] with a [[specific rotation]] of [α]<sub>D</sub>=–166.4° ((−)-nicotine). The [[dextrorotatory]] form, (+)-nicotine is physiologically less active than (−)-nicotine. (−)-nicotine is more toxic than (+)-nicotine.<ref>{{cite book | vauthors = Gause GF |title=Optical Activity and Living Matter|chapter-url=https://archive.org/stream/opticalactivityl00gauz/opticalactivityl00gauz_djvu.txt| veditors = Luyet BJ |publisher=Biodynamica|location= Normandy, Missouri |year=1941|chapter=Chapter V: Analysis of various biological processes by the study of the differential action of optical isomers|volume=2|series= A series of monographs on general physiology}}</ref> The salts of (−)-nicotine are usually dextrorotatory; this conversion between levorotatory and dextrorotatory upon protonation is common among alkaloids.<ref name="library.sciencemadness.org"/> The hydrochloride and sulfate salts become optically inactive if heated in a closed vessel above 180&nbsp;°C.<ref name="library.sciencemadness.org">{{cite book | vauthors = Henry TA | title = The Plant Alkaloids | publisher = The Blakiston Company | location = Philadelphia, Toronto | edition = 4th | year = 1949 | url = http://library.sciencemadness.org/library/books/the_plant_alkaloids.pdf |pages= 36–43 }}</ref> [[Anabasine]] is a [[structural isomer]] of nicotine, as both compounds have the [[molecular formula]] {{chem2|auto=1|C10H14N2}}.

Nicotine that is found in natural tobacco is primarily (99%) the S-enantiomer.<ref name="Enantiomeric composition of nicotin">{{cite journal | vauthors = Zhang H, Pang Y, Luo Y, Li X, Chen H, Han S, Jiang X, Zhu F, Hou H, Hu Q | title = Enantiomeric composition of nicotine in tobacco leaf, cigarette, smokeless tobacco, and e-liquid by normal phase high-performance liquid chromatography | journal = Chirality | volume = 30 | issue = 7 | pages = 923–931 | date = July 2018 | pmid = 29722457 | doi = 10.1002/chir.22866 }}</ref>  Conversely, the most common chemistry synthetic methods for generating nicotine yields a product that is approximately equal proportions of the S- and R-enantiomers.<ref>{{cite journal | vauthors = Hellinghausen G, Lee JT, Weatherly CA, Lopez DA, Armstrong DW | title = Evaluation of nicotine in tobacco-free-nicotine commercial products | journal = Drug Testing and Analysis | volume = 9 | issue = 6 | pages = 944–948 | date = June 2017 | pmid = 27943582 | doi = 10.1002/dta.2145 }}</ref> This suggests that tobacco-derived and synthetic nicotine can be determined by measuring the ratio of the two different enantiomers, although means exist for adjusting the relative levels of the enantiomers or performing a synthesis that only leads to the S-enantiomer. There is limited data on the relative physiological effects of these two enantiomers, especially in people. However, the studies to date indicate that (S)-nicotine is more potent than (R)-nicotine and (S)-nicotine causes stronger sensations or irritation than (R)-nicotine. Studies have not been adequate to determine the relative addictiveness of the two enantiomers in people. 
[[File:Nicotine benzoate.svg|thumb|class=skin-invert-image|Structure of protonated nicotine (left) and structure of the counterion benzoate (right). This combination is used in some vaping products to increase nicotine delivery to the lung.]]
[[Construction of electronic cigarettes#Pod mods|Pod mod]] electronic cigarettes use nicotine in the form of a [[nicotine salt|protonated nicotine]], rather than [[free base|free-base]] nicotine found in earlier generations.<ref name=JenssenBoykan2019>{{cite journal | vauthors = Jenssen BP, Boykan R | title = Electronic Cigarettes and Youth in the United States: A Call to Action (at the Local, National and Global Levels) | journal = Children | volume = 6 | issue = 2 | page = 30 | date = February 2019 | pmid = 30791645 | pmc = 6406299 | doi = 10.3390/children6020030| doi-access = free }}{{CC-notice|cc=by4|url=https://www.mdpi.com/2227-9067/6/2/30/htm|author(s)= Jenssen BP, Boykan R }}</ref>

===Preparation===
The first laboratory preparation of nicotine (as its [[racemate]]) was described in 1904.<ref name=Pictet>{{cite journal |title=Synthese des Nicotins |trans-title=Synthesis of nicotine |language=de |year=1904 | vauthors=Pictet A, Rotschy A |journal=Berichte der Deutschen Chemischen Gesellschaft |volume=37 |issue=2 |pages=1225–1235 |doi=10.1002/cber.19040370206 |url=https://zenodo.org/record/1426104 }}</ref>
[[File:Nicotine synthesis 1904.svg|650px|class=skin-invert-image]]
The starting material was an N-substituted [[pyrrole]] derivative, which was heated to convert it by a [[Sigmatropic reaction|[1,5] sigmatropic shift]] to the [[isomer]] with a carbon bond between the pyrrole and pyridine rings, followed by [[methylation]] and selective reduction of the pyrrole ring using tin and hydrochloric acid.<ref name=Pictet/><ref>{{cite journal |doi=10.1002/hlca.200490241 |title=A New Approach to Nicotine: Symmetry Consideration for Synthesis Design |year=2004 | vauthors = Ho TL, Kuzakov EV |journal=Helvetica Chimica Acta |volume=87 |issue=10 |pages=2712–2716 }}</ref> Many other syntheses of nicotine, in both racemic and chiral forms have since been published.<ref>{{cite journal |doi=10.1002/slct.202104425 |title=Research Progress in the Pharmacological Effects and Synthesis of Nicotine |year=2022 | vauthors = Ye X, Zhang Y, Song X, Liu Q |journal=ChemistrySelect |volume=7 |issue=12 |s2cid=247687372 }}</ref>

===Biosynthesis===
[[File:Nicotine biosynthesis june 2012.png|thumb|300px|class=skin-invert-image|Nicotine biosynthesis]]
The biosynthetic pathway of nicotine involves a coupling reaction between the two cyclic structures that comprise nicotine. Metabolic studies show that the [[pyridine]] ring of nicotine is derived from [[nicotinic acid]] the [[pyrrolidine]] is derived from ''N''-methyl-Δ<sup>1</sup>-pyrrollidium cation.<ref>{{cite journal | vauthors = Lamberts BL, Dewey LJ, Byerrum RU | title = Ornithine as a precursor for the pyrrolidine ring of nicotine | journal = Biochimica et Biophysica Acta | volume = 33 | issue = 1 | pages = 22–6 | date = May 1959 | pmid = 13651178 | doi = 10.1016/0006-3002(59)90492-5 }}</ref><ref>{{cite journal |doi=10.1021/ja01495a059 |title=The Biosynthesis of Nicotine from Isotopically Labeled Nicotinic Acids |year=1960 |vauthors=Dawson RF, Christman DR, d'Adamo A, Solt ML, Wolf AP |journal=Journal of the American Chemical Society |volume=82 |issue=10 |pages=2628–2633|bibcode=1960JAChS..82.2628D }}</ref> Biosynthesis of the two component structures proceeds via two independent syntheses, the NAD pathway for nicotinic acid and the tropane pathway for ''N''-methyl-Δ<sup>1</sup>-pyrrollidium cation.

The NAD pathway in the genus ''[[Nicotiana]]'' begins with the oxidation of aspartic acid into α-amino succinate by aspartate oxidase (AO). This is followed by a condensation with [[glyceraldehyde-3-phosphate]] and a cyclization catalyzed by quinolinate synthase (QS) to give [[quinolinic acid]]. Quinolinic acid then reacts with phosphoribosyl pyrophosphate catalyzed by quinolinic acid phosphoribosyl transferase (QPT) to form nicotinic acid mononucleotide (NaMN). The reaction now proceeds via the NAD salvage cycle to produce nicotinic acid via the conversion of [[nicotinamide]] by the enzyme [[nicotinamidase]].{{citation needed|date=May 2021}}

The ''N''-methyl-Δ<sup>1</sup>-pyrrollidium cation used in the synthesis of nicotine is an intermediate in the synthesis of tropane-derived alkaloids. Biosynthesis begins with [[decarboxylation]] of [[ornithine]] by [[ornithine decarboxylase]] (ODC) to produce [[putrescine]]. Putrescine is then converted into ''N''-methyl putrescine via [[methylation]] by SAM catalyzed by [[Putrescine N-methyltransferase|putrescine ''N''-methyltransferase]] (PMT). ''N''-methyl putrescine then undergoes [[deamination]] into 4-methylaminobutanal by the ''N''-methyl putrescine oxidase (MPO) enzyme, 4-methylaminobutanal then spontaneously cyclize into ''N''-methyl-Δ<sup>1</sup>-pyrrollidium cation.{{citation needed|date=May 2021}}

The final step in the synthesis of nicotine is the coupling between ''N''-methyl-Δ<sup>1</sup>-pyrrollidium cation and nicotinic acid. Although studies conclude some form of coupling between the two component structures, the definite process and mechanism remains undetermined. The current agreed theory involves the conversion of nicotinic acid into 2,5-dihydropyridine through 3,6-dihydronicotinic acid. The 2,5-dihydropyridine intermediate would then react with ''N''-methyl-Δ<sup>1</sup>-pyrrollidium cation to form [[enantiomer]]ically pure (−)-nicotine.<ref name=plant-meta>{{cite book | veditors = Ashihara H, Crozier A, Komamine A |title=Plant metabolism and biotechnology |date=7 June 2011 |publisher=Wiley |location=Cambridge |isbn=978-0-470-74703-2}}{{page needed|date=December 2013}}</ref>

===Detection in body fluids===
Nicotine can be quantified in blood, plasma, or urine to confirm a diagnosis of poisoning or to facilitate a medicolegal death investigation. Urinary or salivary cotinine concentrations are frequently measured for the purposes of pre-employment and health insurance medical screening programs. Careful interpretation of results is important, since passive exposure to cigarette smoke can result in significant accumulation of nicotine, followed by the appearance of its metabolites in various body fluids.<ref>{{cite book |vauthors=Benowitz NL, Hukkanen J, Jacob P |volume=192 |issue=192 |pages=29–60 |date=1 January 2009 |pmid=19184645 |pmc=2953858 |doi=10.1007/978-3-540-69248-5_2 |isbn=978-3-540-69246-1 |series=Handbook of Experimental Pharmacology |title=Nicotine Psychopharmacology |chapter=Nicotine Chemistry, Metabolism, Kinetics and Biomarkers }}</ref><ref>{{cite book| vauthors = Baselt RC |title=Disposition of Toxic Drugs and Chemicals in Man|year=2014|publisher=Biomedical Publications|isbn=978-0-9626523-9-4|edition=10th|pages=1452–6}}</ref> Nicotine use is not regulated in competitive sports programs.<ref>{{cite journal | vauthors = Mündel T, Jones DA | title = Effect of transdermal nicotine administration on exercise endurance in men | journal = Experimental Physiology | volume = 91 | issue = 4 | pages = 705–13 | date = July 2006 | pmid = 16627574 | doi = 10.1113/expphysiol.2006.033373 | s2cid = 41954065 | doi-access = free }}</ref>

===Methods for analysis of enantiomers===
Methods for measuring the two enantiomers are straightforward and include normal-phase liquid chromatography,<ref name="Enantiomeric composition of nicotin"/> liquid chromatography with a chiral column.<ref>{{cite journal | vauthors = Hellinghausen G, Roy D, Wang Y, Lee JT, Lopez DA, Weatherly CA, Armstrong DW | title = A comprehensive methodology for the chiral separation of 40 tobacco alkaloids and their carcinogenic E/Z-(R,S)-tobacco-specific nitrosamine metabolites | journal = Talanta | volume = 181 | pages = 132–141 | date = May 2018 | pmid = 29426492 | doi = 10.1016/j.talanta.2017.12.060 }}</ref> However, since methods can be used to alter the two enantiomers, it may not be possible to distinguish tobacco-derived from synthetic nicotine simply by measuring the levels of the two enantiomers. A new approach uses hydrogen and deuterium nuclear magnetic resonance to distinguish tobacco-derived and synthetic nicotine based on differences the substrates used in the natural synthetic pathway performed in the tobacco plant and the substrates most used in synthesis.<ref>{{cite journal | vauthors = Liu B, Chen Y, Ma X, Hu K | title = Site-specific peak intensity ratio (SPIR) from 1D <sup>2</sup>H/<sup>1</sup>H NMR spectra for rapid distinction between natural and synthetic nicotine and detection of possible adulteration | journal = Analytical and Bioanalytical Chemistry | volume = 411 | issue = 24 | pages = 6427–6434 | date = September 2019 | pmid = 31321470 | doi = 10.1007/s00216-019-02023-6 | s2cid = 197593505 }}</ref> Another approach measures the carbon-14 content which also differs between natural and laboratory-based tobacco.<ref>{{cite journal | vauthors = Cheetham AG, Plunkett S, Campbell P, Hilldrup J, Coffa BG, Gilliland S, Eckard S | title = Analysis and differentiation of tobacco-derived and synthetic nicotine products: Addressing an urgent regulatory issue | journal = PLOS ONE | volume = 17 | issue = 4 | pages = e0267049 | date = 2022-04-14 | pmid = 35421170 | pmc = 9009602 | doi = 10.1371/journal.pone.0267049 | bibcode = 2022PLoSO..1767049C | veditors = Greenlief CM | doi-access = free }}</ref> These methods remain to be fully evaluated and validated using a wide range of samples.

===Analogues and derivatives===
[[Structural analog|Analogue]]s and [[chemical derivative|derivative]]s of nicotine are known.<ref name="Breining2004">{{cite journal | vauthors = Breining SR | title = Recent developments in the synthesis of nicotinic acetylcholine receptor ligands | journal = Curr Top Med Chem | volume = 4 | issue = 6 | pages = 609–629 | date = 2004 | pmid = 14965298 | doi = 10.2174/1568026043451131 | url = }}</ref><ref name="VaggChapman2005">{{cite journal | vauthors = Vagg R, Chapman S | title = Nicotine analogues: a review of tobacco industry research interests | journal = Addiction | volume = 100 | issue = 5 | pages = 701–712 | date = May 2005 | pmid = 15847628 | doi = 10.1111/j.1360-0443.2005.01014.x | url = }}</ref><ref name="PogockiRumanDanilczuk2007">{{cite journal | vauthors = Pogocki D, Ruman T, Danilczuk M, Danilczuk M, Celuch M, Wałajtys-Rode E | title = Application of nicotine enantiomers, derivatives and analogues in therapy of neurodegenerative disorders | journal = Eur J Pharmacol | volume = 563 | issue = 1–3 | pages = 18–39 | date = June 2007 | pmid = 17376429 | doi = 10.1016/j.ejphar.2007.02.038 | url = }}</ref><ref name="PandaAlbano2021">{{cite journal | vauthors = Panda B, Albano G | title = Synthetic Methods for the Preparation of Conformationally Restricted Analogues of Nicotine | journal = Molecules | volume = 26 | issue = 24 | date = December 2021 | page = 7544 | pmid = 34946630 | pmc = 8706964 | doi = 10.3390/molecules26247544 | doi-access = free | url = }}</ref><ref name="EffahSunLin2025">{{cite journal | vauthors = Effah F, Sun Y, Lin K, Rahman I | title = A comparative toxicological evaluation of emerging nicotine analogs 6-methyl nicotine and nicotinamide: a scoping review | journal = Arch Toxicol | volume = 99| issue = 4| pages = 1333–1340| date = February 2025 | pmid = 39937258 | doi = 10.1007/s00204-025-03960-1 | bibcode = 2025ArTox..99.1333E | url = }}</ref> Examples include [[altinicline]], [[anabasine]], [[anatabine]], [[altinicline]], [[arecoline]], [[6-chloronicotine]], [[cotinine]], [[cytisine]], [[dianicline]], [[epibatidine]], [[levamisole]], [[RJR-2429]], [[TC-1698]], [[UB-165]], and [[varenicline]], among others.<ref name="BoidoTassoBoido2003">{{cite journal | vauthors = Boido CC, Tasso B, Boido V, Sparatore F | title = Cytisine derivatives as ligands for neuronal nicotine receptors and with various pharmacological activities | journal = Farmaco | volume = 58 | issue = 3 | pages = 265–277 | date = March 2003 | pmid = 12620422 | doi = 10.1016/S0014-827X(03)00017-X | url = }}</ref><ref name="Breining2004" />